It has long been recognized that dysregulated inflammation causes many human diseases. The systemic inflammatory response, best associated with infections (termed sepsis), is a common and life- threatening example of hyperinflammatory damage. Very little is known about what regulates an appropriate versus excessive inflammatory response, or how to manipulate inflammation to prevent damage. The goal of this proposal is to understand how mutations in a protein called NLRC4 result in a human sepsis-like phenotype known as Macrophage Activation Syndrome (MAS). When activated, NLRC4 triggers the formation of a large protein complex called the inflammasome. Inflammasomes drive inflammation throughout the body by activating pro-inflammatory cytokines and inducing an inflammatory form of cell death. Intriguingly, in addition to MAS, NLRC4 mutations cause early-onset intestinal inflammation that resolves in infancy. How these mutations result in this specific hyperinflammatory syndrome is unknown. Understanding this mechanism will provide important insights into basic inflammasome function, the risk factors for hyperinflammatory damage, the different immunologic flavors of systemic inflammation, and the ways we might intervene to prevent damage. Aim 1 of this proposal will examine the mechanisms by which NLRC4 mutations cause inflammatory damage. To facilitate this, NLRC4 mutations will be compared to mutations in a related inflammasome component called NLRP3. NLRP3 hyperactivity also causes inflammasome formation, but a very different inflammatory syndrome. This aim will focus on how these different inflammasomes function in the same cell type, as well as the systemic effects of which cells have active inflammasomes. The unique role of inflammasomes in intestinal epithelial cells may inform the transient gut phenotype unique to NLRC4-MAS. Aim 2 will explore an important but enigmatic finding: extraordinary and chronic elevation of the inflammasome- dependent cytokine IL-18 occurs in MAS (regardless of NLRC4 mutations) but not NLRP3-related diseases. This aim will examine how chronic exposure to high IL-18 primes the immune system for an MAS-like response to danger signals, looking both systemically and in-depth at IL-18 responsive cells. Completion of these aims, along with the training opportunities included as part of this proposal, will establish the necessary foundation for a career as an independent translational investigator.